Lower endogenous melatonin production is associated with a higher risk of insulin resistance and type 2 diabetes, a higher risk of hypertension, and a higher degree of systemic inflammation in humans. Animal and in vitro experiments, observational studies, and uncontrolled interventions suggest that exogenous melatonin supplementation, particularly controlled-release melatonin, may ameliorate these cardiovascular risk factors. However, rigorously controlled trials using nighttime administration of controlled-release melatonin (to mimic normal melatonin physiology) are lacking. Obese, pre-diabetic individuals (BMI ? 30 kg/m2; HbA1c, 5.7-6.5%) are at risk of having increased insulin resistance, decreased pancreatic ?-islet function, elevated blood pressure, and systemic inflammation; in addition, they also have markedly reduced endogenous melatonin secretion. Such individuals therefore represent an ideal study population to examine the effects of melatonin on these risk factors for cardiovascular disease. We plan to conduct a double-blind, placebo-controlled randomized clinical trial, in which we will enroll 120 subjects with obesity (BMI ? 30 kg/m2) and pre-diabetes (HbA1C, 5.7-6.4%). Subjects will be randomly assigned 1:1 to receive either placebo or 2 mg of controlled- release melatonin, taken orally every evening before bed for 12 weeks. We will evaluate the effect of melatonin on the co-primary endpoints of peripheral insulin resistance using a hyperinsulinemic euglycemic clamp and pancreatic ?-islet cell function using a hyperglycemic clamp. The secondary endpoint will be mean 24-hour ambulatory blood pressure and the tertiary endpoint will be inflammation marked especially by levels of the CC family of chemokines. From a scientific standpoint, this trial will provide the fist experimental human data regarding the effects of melatonin supplementation on peripheral insulin resistance, pancreatic ?-islet cell function, and inflammation. From a public health standpoint, the results of this trial will inform strategies and future trials designed to prevent he incidence of diabetes, hypertension, and cardiovascular disease.